Performance of plasma phosphorylated tau 181 and 217 in the community

Mielke, Michelle M.; Dage, Jeffrey L.; Frank, Ryan D.; Algeciras‐Schimnich, Alicia; Knopman, David S.; Lowe, Val J.; Bu, Guojun; Vemuri, Prashanthi; Graff‐Radford, Jonathan; Jack, Clifford R.; Petersen, Ronald C.

doi:10.1038/s41591-022-01822-2

Cited by 181 publications

(246 citation statements)

References 33 publications

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“…Previous studies suggested plasma p-tau levels can be affected by other diseases or factors. Multiple comorbidities, including a history of chronic kidney disease (CKD), hypertension, myocardial infarction (MI) and stroke, were found to be associated with elevated plasma p-tau181 and p-tau217 levels (Mielke et al, 2022 ). These confounding factors may influence physiological processes.…”

Section: Discussionmentioning

confidence: 99%

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Plasma tau proteins for the diagnosis of mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis

Chen

Niu

Wang

et al. 2022

Front. Aging Neurosci.

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ObjectiveDetecting plasma tau biomarkers used to be impossible due to their low concentrations in blood samples. Currently, new high-sensitivity assays made it a reality. We performed a systematic review and meta-analysis in order to test the accuracy of plasma tau protein in diagnosing Alzheimer's disease (AD) or mild cognitive impairment (MCI).MethodsWe searched PubMed, Cochrane, Embase and Web of Science databases, and conducted correlation subgroup analysis, sensitivity analysis and publication bias analysis using R Programming Language.ResultsA total of 56 studies were included. Blood t-tau and p-tau levels increased from controls to MCI to AD patients, and showed significant changes in pairwise comparisons of AD, MCI and normal cognition. P-tau217 was more sensitive than p-tau181 and p-tau231 in different cognition periods. In addition, ultrasensitive analytical platforms, immunomagnetic reduction (IMR), increased the diagnostic value of tau proteins, especially the diagnostic value of t-tau.ConclusionBoth t-tau and p-tau are suitable AD blood biomarkers, and p-tau217 is more sensitive than other tau biomarkers to differentiate MCI and AD. Detection techniques also have an impact on biomarkers' results. New ultrasensitive analytical platforms of IMR increase the diagnostic value of both t-tau and p-tau biomarkers.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, registration number: CRD42021264701.

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Section: Discussionmentioning

confidence: 99%

“…These confounding factors may influence physiological processes. For example, CKD reduces clearance of proteins in the blood, leading to the high p-tau and t-tau levels (Mielke et al, 2022 ). A history of stroke implies neuronal damage.…”

Section: Discussionmentioning

confidence: 99%

Plasma tau proteins for the diagnosis of mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis

Chen

Niu

Wang

et al. 2022

Front. Aging Neurosci.

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“…Of the included studies reporting P-tau measures, 13 explicitly evaluated P-tau181, and it is an assumption (as detailed in Section 2.2 ) that for the four studies where this was not explicitly stated only P-tau181 residues could have been evaluated. Both P-tau181 and P-tau217 are currently being shown to have strong potential to differentiate patients with AD from other neurodegenerative disorders [ 62 ] and the relationship between P-tau181, P-tau217, and amyloid burden is also being examined [ 27 ]. In many respects, changes in P-tau217 levels appear to parallel P-tau181 changes, and P-tau181 remains a valuable marker [ 27 ]; it will, however, be interesting to see how P-tau217 performs (including the Aβ1-42/P-tau217 ratio) in future meta-analyses for the purpose of predicting progression from MCI to AD.…”

Section: Discussionmentioning

confidence: 99%

“…P-tau levels correlate with cortical tangle formation and reflect the phosphorylation state of tau [ 21 , 26 ]. Elevated concentrations of P-tau181 were previously associated with rapid cognitive decline in AD [ 24 ], and more recently the P-tau217 residue has started to be evaluated alongside P-tau181 as an indicator of amyloid and tau pathology in clinical settings [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

A Systematic Review and Meta-Analysis of Cerebrospinal Fluid Amyloid and Tau Levels Identifies Mild Cognitive Impairment Patients Progressing to Alzheimer’s Disease

Brettschneider

Collingwood

2022

Biomedicines

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Reported levels of amyloid-beta and tau in human cerebrospinal fluid (CSF) were evaluated to discover if these biochemical markers can predict the transition from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD). A systematic review of the literature in PubMed and Web of Science (April 2021) was performed by a single researcher to identify studies reporting immunologically-based (xMAP or ELISA) measures of CSF analytes Aβ(1-42) and/or P-tau and/or T-tau in clinical studies with at least two timepoints and a statement of diagnostic criteria. Of 1137 screened publications, 22 met the inclusion criteria for CSF Aβ(1-42) measures, 20 studies included T-tau, and 17 included P-tau. Six meta-analyses were conducted to compare the analytes for healthy controls (HC) versus progressive MCI (MCI_AD) and for non-progressive MCI (Stable_MCI) versus MCI_AD; effect sizes were determined using random effects models. The heterogeneity of effect sizes across studies was confirmed with very high significance (p < 0.0001) for all meta-analyses except HC versus MCI_AD T-tau (p < 0.05) and P-tau (non-significant). Standard mean difference (SMD) was highly significant (p < 0.0001) for all comparisons (Stable_MCI versus MCI_AD: SMD [95%-CI] Aβ(1-42) = 1.19 [0.96,1.42]; T-tau = −1.03 [−1.24,−0.82]; P-tau = −1.03 [−1.47,−0.59]; HC versus MCI_AD: SMD Aβ(1-42) = 1.73 [1.39,2.07]; T-tau = −1.13 [−1.33,−0.93]; P-tau = −1.10 [−1.23,−0.96]). The follow-up interval in longitudinal evaluations was a critical factor in clinical study design, and the Aβ(1–42)/P-tau ratio most robustly differentiated progressive from non-progressive MCI. The value of amyloid-beta and tau as markers of patient outcome are supported by these findings.

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“…The relationship between plasma P-tau181 concentration and comorbidities, demographic factors and biological information collected at baseline in the BALTAZAR cohort was investigated using a linear regression approach 22,23 . APOE status, creatinine and eGFR could be identified as impacting the most plasma P-tau181 (Figure 1B).…”

Section: Impact Of Comorbidities and Covariates On P-tau181 Concentra...mentioning

confidence: 99%

Plasma phosphorylated tau 181 predicts amyloid status and conversion to dementia stage dependent on renal function

Lehmann

Schraen‐Maschke

Vidal

et al. 2022

Preprint

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BackgroundPlasma P-tau181 is associated with tau and amyloid pathology in Alzheimer’s disease (AD). Its use as a biomarker for the detection of AD (along the disease continuum, from preclinical to mild cognitive impairment (MCI) and dementia) is increasingly established, as is its prognostic value. Further validation in different settings of use is still needed, as well as investigation of confounding factors that might indirectly influence its blood concentration.MethodsThis study is ancillary to the prospective multicenter BALTAZAR cohort that enrolled patients with MCI according to Petersen criteria. Amyloid-positive (Aβ+) status was based on assessment of the cerebrospinal fluid (CSF) Aβ1-42/Aβ1-40 ratio, and participants were examined for conversion to dementia for up to three years. Plasma Ptau-181 was measured using an ultrasensitive assay and its diagnostic performance for Aβ+ and conversion to dementia were studied, as well as evaluation of the impact of comorbidities and biological confounders.FindingsAmong 476 MCI participants (mean MMSE score of 26·4 [SD 2·5] and 39·8% carrying APOE ε4), 67% were Aβ+ and 30% developed dementia (95% probable AD) at a mean of 14·6 [SD 8·2] months after the baseline. Independently of age, sex, and APOEε4, plasma P-tau181 was increased significantly by 30% between non-converters and converters (2·9 [SD 1·4] vs. 3·8 [SD 1·5] pg/mL, p<0·0001) and by 50% between Aβ- and Aβ+ (2·6 [SD 1·4] vs. 3·9 [SD 1·4] pg/mL, p<0·0001). Logistic regression was used to compare conversion and Aβ+ detection combining age, sex, APOEε4 status and MMSE without or with the addition of plasma P-tau181 which significantly improves performance (AUC 0·691 to 0·744 for conversion and 0·786 to 0·849 for Aβ+). CSF P-tau181 did not perform better in the same setting. Using a linear regression approach, chronic kidney disease (CKD), creatinine and glomerular filtration rate were independently associated with plasma P-tau181 concentrations, thereby altering the optimal cutpoints for Aβ+ or conversion to dementia detection.InterpretationPlasma P-tau181 effectively detects Aβ+ and conversion to dementia in a manner similar to CSF P-tau181, making this blood biomarker central to AD management. However, renal function significantly alters concentrations and will induce diagnostic error if not systematically taken into account.

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Performance of plasma phosphorylated tau 181 and 217 in the community

Cited by 181 publications

References 33 publications

Plasma tau proteins for the diagnosis of mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis

Plasma tau proteins for the diagnosis of mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis

A Systematic Review and Meta-Analysis of Cerebrospinal Fluid Amyloid and Tau Levels Identifies Mild Cognitive Impairment Patients Progressing to Alzheimer’s Disease

Plasma phosphorylated tau 181 predicts amyloid status and conversion to dementia stage dependent on renal function

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